Bacterial antibiotic resistance has become one of the most serious threats to modern health care. Cohen, Science 1992, 257: 1051-1055 discloses that infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Neu, Science 1992, 257: 1064-1073 discloses that the need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents rendering them quickly ineffective. Anderson, Nature America 1999, 5: 147-149 refers to the spread of antibiotic resistance as a pandemic and asserts that a solution to the growing public health threat will require an interdisciplinary approach.
The present crisis has prompted various efforts to elucidate the mechanisms responsible for bacterial resistance, Coulton et al., Progress in Medicinal Chemistry 1994, 31: 297-349 teaches that the widespread use of penicillins and cephalosporins has resulted in the emergence of β-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the β-lactam ring common to numerous presently used antibiotics. More recently, Dudley, Pharmacotherapy 1995, 15: 9S-14S has disclosed that resistance mediated by β-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance. Clavulanic acid, which is a metabolite of Streptomyces clavuligerus, and two semi-synthetic inhibitors, sulbactam and tazobactam are presently available semi-synthetic or natural product β-lactamase inhibitors. U.S. Pat. No. 5,698,577, U.S. Pat. No. 5,510,343, U.S. Pat. No. 6,472,406 and Hubschwerlen et al., J. Med. Chem. 1998, 41: 3961 and Livermore et al., J. Med. Chem. 1997, 40: 335-343, disclose certain synthetic β-lactamase inhibitors.
Other references of interest are:
US 2003/0199541 A1 discloses certain azabicyclic compounds including certain 7-oxo-6-diazabicyclic[3.2.1]octane-2-carboxamides and their use as anti-bacterial agents.
US 2004/0157826 A1 discloses certain heterobicyclic compounds including certain diazepine carboxamide and diazepine carboxylate derivatives and their use as anti-bacterials and β-lactamase inhibitors.
WO 2008/039420 A2 discloses certain 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfooxy-2-carboxamides and their use of beta-lactamse inhibitors.
Poole, Cell. Mol. Life Sci. 2004, 61: 2200-2223, provides a review of the resistance of bacterial pathogens to β-lactam antibiotics and approaches for overcoming resistance.
The currently available β-lactamase inhibitors are insufficient to counter the constantly increasing diversity of β-lactamases. There is, therefore, a need for new β-lactamase inhibitors.